Act Nerv Super Rediviva 2013; 55(3): 125134

R E V I E W A R T I C L E
Activitas Nervosa Superior Rediviva Volume 55 No. 3 2013
Sex differences in pain perception and interpretation
Richard Rokyta, Anna Yamamotov
Charles University in Prague, Third Faculty of Medicine, Department of Normal, Pathological and Clinical
Physiology, Prague, Czech Republic.
Correspondence to: Prof. Richard Rokyta, MD., DSc., Charles University in Prague, Third Faculty of Medicine,
Department of Normal, Pathological and Clinical Physiology, Ke Karlovu 4, 120 00 Praha 2, Czech Republic.
tel/fax: +420 224923827; e-mail: richard.rokyta@lf3.cuni.cz
Submitted: 2013-09-16 Accepted: 2013-09-28 Published online: 2013-10-03
Key words:
evidence-based medicine; pain; treatment; sex differences
Act Nerv Super Rediviva 2013; 55(3): 125134 ANSR550313A05 2013 Act Nerv Super Rediviva
Abstract
This study tries to explain the importance of sex differences in the perception of pain and
its treatment. The study examines sex differences not only between men and women, but
more generally between males and females. The study deals with both experimental and
clinical findings. Generally speaking, women have lower pain thresholds and they also
differ in their response to analgesic therapy (e.g. opioids). We focused our attention on a
description of painful symptoms and syndromes, their pathophysiology and treatment.
This study aims to contribute to a better understanding of the pathophysiology of chronic
pain, particularly since it affects about 30% of the population. Proper treatment should
be based on the pathophysiology and pharmacology of pain phenomena. The study also
presents therapeutic experiences and possible clinical applications. Our article intends to
promote good clinical practice based on evidence-based medicine.
Introduction
Treatment of chronic pain, which affects an aver-
age of 30% of the population, is significant in terms of
medical practice. Individual medical disciplines try to
develop consensus-recommended procedures (guide-
lines) that take into account all factors that can affect
treatment. One of the important factors that can affect
proper treatment of chronic pain is gender differences.
In this article we analyze different pathophysiological
mechanisms associated with pain perception in terms
of gender differences from the standpoint of general
knowledge and principles of evidence based medi-
cine. Additionally, we describe the current status of
pain treatment and clinical experiences. We also eval-
uate experimental and clinical findings in an effort to
determine what new information has application in
the clinical setting.
The Working Group Sex Gender and Pain IASP
(Greenspan et al 2007) developed a consensus report
on the study of sex differences in pain and analgesia
which underlines the following principles:
The relevance and importance of studying sex
differences
The importance of experimental studies of sex dif-
ferences in pain and in analgesia
Questions whether sex differences are due to
gonadal differences. The answer is yes, but only
partially
Testing the estrous cycle in animal studies, the
influence of the menstrual cycle in humans, hor-
monal manipulation in animal studies and in
human studies
Which types of pain are suitable for the study of sex
differences in animals and humans
Deals with clinical and psychosocial studies of sex
differences in pain and analgesia
Defines these differences: age, race, ethnicity and
culture, history, the difference between patients and
controls in the perception of pain, comorbidity, dis-
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Richard Rokyta, Anna Yamamotov
ability, treatment, natural variability, hope, struggles
with pain, mood and other psychological factors
Deals with the temporal summation of pain, opioid
analgesia and the future of this study, which is con-
sidered relevant
We also briefly address the abovementioned issues.
This was linked to the Global year of pain in women
(2010), which declared the IASP and proclaimed it to be
a very important stage in the study of pain (Collett &
Berkley 2007).
Epidemiology of pain
When we were finishing this article, the European
Journal of Pain published the study Gender role after
experimental pain responses: A systematic review
with meta-analysis by Alabas et al (2012a), in which
the authors performed a meta-analysis of studies from
years 19502011.
They documented the prevalence of four chronic
pain conditions among 131,535 adults in Canada. The
prevalence of depression in women was 9.1%, which
was two times higher than in men (5%). One third of
women patients suffered from chronic pain mostly
fibromyalgia, arthritis and rheumatism, back pain
and migraines (Denegar et al 2012). The prevalence of
depression in people with chronic pain was 11.3% vs.
5.3% in those without chronic pain. Depression and
chronic pain are significant sources of disability, espe-
cially in women.
Tsai (2007) described large differences in depres-
sive tendencies among Chinese adults with osteoar-
thritic knees. Women were more prone to depression
and more often afflicted with pain than men. Women
who could not walk tended to express their feelings
about the problem more than men. Psychological risk
is an important factor to consider before knee replace-
ment. Pessimism has been found to make pain much
worse and can delay recovery for up to two years, in
some cases, after total knee arthroplasty (Tsai 2007).
Normally, women recover faster after knee arthroplasty
than men, although they have greater functional limita-
tions during the surgical period; nonetheless, they heal
faster than men and have better improvement scores.
Research into pain in humans
Men and women are different and this difference
often manifests as physical factors such as body size
and thickness of the skin, as well as different neuronal
organization and density of opioid receptors. Of course,
there are also psychological and cultural differences, so
it is impossible to conclude that any one factor is much
more important than the others.
Pain perception
Women are more sensitive to pain than men. Among
78 clinical pain states, half of them are more common
in women, and only one-third are more common in
men (Berkley 1997; Fillingim et al 1999, 2009; Fillingim
2005). Women have lower thresholds to experimentally
induced somatic pain stimuli, greater ability to discrim-
inate between stimuli, higher pain scores, and lower
tolerance to pain than men (Gallagher 2012; Pool et al
2007). Peripheral vasoconstriction during prolonged
cold nociceptive stimulation generated more response
in women than in men, which means that women may
be much more sensitive to cold, but not heat stimula-
tion, than men (Manning & Fillingim 2002).
When the threshold for mechanical pain was tested
in healthy volunteers it was shown that the threshold of
pain pressure points was lower in women than in men,
and similar changes were also observed in fibromyalgia.
Recovery after fibromyalgia pain was faster in men than
in women; women are also known to go through dif-
ferent phases of pain relative to their menstrual cycle
(Graven-Nielsen & Arendt-Nielsen 2007).
Kakeda & Ishikawa (2011) studied the effect of sweet
stimuli on pain perception in adults in a randomized
study. They studied 20 men and 20 women; half of
them received a 24% sucrose solution and the other half
received distilled water during immersion of their hand
in cold water. In men, contrary to women, the sucrose
solution in their mouth increased the latency of pain
sensations compared to distilled water; however, tol-
erance to pain did not differ. This analgesic effect was
particularly evident in males, which was rather surpris-
ing since women are thought to be very responsive to
sweet tastes. This finding has potential use in the man-
agement of acute pain in men.
Hypoalgesia also differs between the sexes. Stress-
induced modulation of pain is associated with different
degrees of activation of neural and endocrine systems
that are sexually dimorphic. Riva et al (2011) showed
that it was easier to recognize pain in women from their
facial expressions than in men and underestimation of
pain was more common in men than in women.
Garcia et al (2007) measured pain thresholds using
pressure points on various parts of the body. Women
had lower pain thresholds compared to men. In all areas
of the body, these differences were expressed more
in control pressure points than at points where pain
originated.
Lund & Lundeberg (2010) studied gender differences
in sensory and pain thresholds after electro-acupunc-
ture application. The pain threshold after acupuncture
was increased in women but unchanged in men. Inter
individual variability was large in both sexes.
Age differences
There is also a difference between adults and children.
Children between 68 years are less sensitive to all pain-
ful stimuli compared to older children, 912 years; on the
other hand there was practically no difference compared
to children 1317 year olds. Sex differences were mini-
mal, if any, during childhood (Blankenburg et al 2010).
127 Act Nerv Super Rediviva Vol. 55 No. 3 2013
Sex differences in pain perception and interpretation
Srivatsava et al (2010) describe the effect of age and
gender on pressure and cold stimulation in the Indian
population. They examined young adults (1725 years
old) and aging men and women (5070 years). The
protocol involved immersion of one hand in cold water
(04 C) for one minute, during which time systolic and
diastolic blood pressures were measured. The increases
in systolic and diastolic blood pressures were higher in
young women than in young men and the differences
were more evident in diastolic pressures. Similarly, in
older groups of both sexes, responses to the cold pres-
sor test were always associated with an increase in both
diastolic and systolic blood pressure but the diastolic
pressure increased more in men than in women.
Painful behavior at extremely low gestational ages
was measured in children with gestational ages less
than 28 weeks. Several physiological parameters were
measured: [1] changes in heart rate and oxygen satura-
tion, and behavioral parameters, [2] facial expression,
facial and body movements and biochemical param-
eters, and [3] cortisol in saliva. A heel prick was used as
the pain stimulus and a change of diapers was used as
the painless stimulus. Four mimic characteristics were
observed: [1] facial expression with pulling eyebrows,
[2] closed eyes, [3] course of nasolabial folds, and [4]
vertical constriction of the mouth that appeared imme-
diately after the heel prick. Facial expressions were
the most sensitive indicator of pain in very premature
infants. Other symptoms such as hands on face and
yawning must be monitored in the future. In this work,
no sex differences were observed in facial expression
in response to pain (Ozawa et al 2011). The effects of
gender were also monitored from the point of view of
hand laterality on the development of pain in human
neonates. Using imaging techniques, it has been shown
that right-sided stimulation induces greater prefrontal
activation than left-sided stimulation. Hand laterality
therefore affects pain perception in neonates although
no sex differences in pain perception have been
observed during this developmental period.
Sex differences in the elderly, with regard to pain
perception, were less pronounced compared to those
that were middle aged.
Neurobiological factors and
pharmacotherapy
Opioids
Men and women differ in their sensitivity to opioid
treatment. Women have lower responses to opioid
agonists and better responses to opioid agonist anal-
gesic (pentazocine) than men (Chen et al 2008).
Beta endorphin modulates adenosine provoked
chest pain in men but not in women. In men, beta
endorphin induces analgesia, while women are more
resistant to modulation (Sadigh et al 2007).
Opioid analgesia is not only dependent on sex
hormones but also on genotype. It does not affected
memory, however, when testing episodic memory,
women had more errors after oxycodone than men
and men had more errors after placebo than women
(Friswell et al 2008).
A clinical study by Li et al (2010b) showed the effects
of gender on the minimal local analgesic concentration
of ropivacaine needed for local anesthesia during ano-
rectal surgery. In women, the effective dose of anesthe-
sia is 31% higher than in men.
When epidural morphine was used, the only side
effect observed was a higher incidence of nausea and
vomiting (47% women, 16% men). Women have more
frequent psychological effects that accompany pain.
Sensitivity, fear and pain are higher in women than in
men (Frew & Drummond 2007).
Placebo effects
There is an important relationship between endoge-
nous opioids and placebo. Some people do not respond
to placebo by increasing endogenous opioid levels and
they have hyperalgesic reactions to psychological dis-
tress. Hyperalgesia is more common in women than in
men. It may explain why cold-induced pain is greater
in women and why they respond more to naltrexone
(Robinson et al 2005).
Men are better placebo responders than women
(Aslaksen et al 2011). After placebo, pain unpleas-
antness was shown to be decreased in males but not
females. This could have been caused by suppression or
reduction of anticipatory stress.
Cicero et al (2012) showed that women suffer more
from pain than men and have worse psychiatric out-
comes in all age groups. It is important to use opioid
therapy correctly in patients who are dependent on opi-
oids because inappropriate treatment may worsen the
pain and potentially exacerbate psychiatric problems.
Sexual hormones
Pain can be modulated by estrogens; estradiol being
the most intensively studied estrogen. Estrogens are
included in the pathophysiology of pain in migraine,
temporomandibular pain and arthritis. Estrogens mod-
ulate the function of the nervous, immune, skeletal and
cardiovascular systems. Estrogens can have both pro-
nociceptive and anti-nociceptive effects depending on
the type of pain and consequently they have both nega-
tive and positive effects (Brsen 2007).
Kumar et al (2010) compared the variation in
responses during experimental pain in women with
menstrual cycles and compared it with a one-month
course of responses in men. Men showed no differences
in responses to pain. Women reported higher pain sen-
sitivity on the 14th day of their menstrual cycles. These
cyclic changes were associated with increased fertility
in a certain period of the menstrual cycle.
Bereiter & Okamoto (2011) demonstrated that
estrogen was associated with the neurobiology of deep
craniofacial pain. Estrogens act both peripherally and
128 Copyright 2013 Activitas Nervosa Superior Rediviva ISSN 1337-933X
Richard Rokyta, Anna Yamamotov
centrally and affect the temporomandibular joint. He
created a new term temporomandibular joint matrix,
which includes estrogen status.
Prof. Aloisi, from the University of Siena (Aloisi et
al 2004), studied changes in pain perception in trans-
sexuals taking sex hormones for development of the
somatic characteristics associated with the opposite
sex. 29% were converting from male to female and 61%
from female to male. In male to female conversion,
after estrogens and anti-androgens treatments, the most
commonly reported pain was headache, breast and
musculoskeletal pain. Women converting to men were
given androgens (Aloisi et al 2011). Gender transforma-
tion induced pains of different origins. Some patients
had more than one type of pain. In some patients, the
pain was already present before the administration of
hormones, but other types of pain appeared in associa-
tion with testosterone.
Clinical findings
Genetic studies indicate not only the significance of sex
differences, but also environmental effects. A predis-
position to develop chronic pain in humans seems to
be mainly associated with neuropathic pain. It includes
trigeminal neuralgia, CRPS, phantom pain, back pain,
menstrual pain, migraine, fibromyalgia, familial rectal
pain syndrome and other peripheral neuropathies. In
most cases these painful conditions appeared to be
determined by multifactorial genetic and epigenetic
factors.
Neuropathic pain
Complex regional pain syndrome (CRPS) is multifacto-
rial and includes disorders of peripheral and autonomic
nerves, the central nervous system, visceral system,
connective tissues, and hormonal systems, all of which
can induce psychological changes. It is impossible to
find a single responsible system.
Bryce et al (2007) showed that the frequency of
spinal cord injury (SCI) is relatively similar in men and
women. Women with SCI have a higher prevalence of
nociceptive pain than men and therefore the use of non-
steroidal anti-inflammatory drugs (NSAID) was higher.
Pro-inflammatory cytokines facilitate neuropathic
pain. They are up-regulated in peripheral nerves,
dorsal root ganglia, and in some areas of the brain after
peripheral nerve injuries. Direct application of exog-
enous inflammatory cytokines causes pain. Blockade
of anti-inflammatory cytokine production reduces pain
behaviors in many experimental models. Measurement
of cytokine levels can identify patients at high risk of
developing chronic pain associated with neuropathic
causes such as peripheral neuropathy or postherpetic
neuralgia. Anti-cytokine medication is important in
the treatment of inflammatory pain, and it may also be
used in certain neuropathies. Anti-cytokine treatment
can stabilize and equalize the ratio between pro- and
anti-inflammatory cytokine levels in specific patients
(Schfers & Sommer 2007).
Fibromyalgia is a sex-linked disease (Lange et al
2010). Diagnosing fibromyalgia correctly is relatively
difficult. In men, fibromyalgia is less frequent but,
unlike in women, it is much easier to diagnose (Katz
et al 2010). Previous experience is important regarding
fibromyalgia outcomes. In patients undergoing mul-
tidisciplinary rehabilitation for pain, successful treat-
ments, which improve physical and emotional function,
often differ between the sexes (Hooten et al 2007).
Back pain
A large part of clinical research is devoted to back pain.
We must take into account the fact that back pain in
men has a psychological trigger more often than in
women (Robinson et al 2004).
A paper by Fillingim et al (2003a), deals with the
clinical characteristics of chronic back pain. In male
patients with back pain, opioids cause affective distress,
which was not present in female patients. On the other
hand, women had higher pain intensity, which has been
cited in a majority of publications. Also myofascicular
pain syndrome, as a source of chronic back pain, was
significantly more common in women.
Back pain, has also been studied from the point of
view of emotive responses and the feelings of patients in
pain. Assessors were nurses. Men expressed more pain
than women but only when the nurse was looking at
them. Addiction to pain often means an escape to pain
(like escape to illness) that is significantly different in
men and women (Watson & Shay 2010).
After the first injection of epidural steroids, for low
back pain, men felt greater pain intensity and unpleas-
antness than women. After two weeks of treatment men
had a greater reduction in pain, depression and dis-
ability than women. When the comparison was made
after two months, gender differences were diminished
(Inman et al 2004). Sex differences are common relative
to shoulder pain (Kindler et al 2011).
Musculoskeletal disorders
Likewise, there are sex differences in the prevalence of
musculoskeletal disorders (Budh et al 2003; Novicoff
& Saleh 2011). Musculoskeletal pain is more common
in women, but men have higher rates of disability. Low
back pain is more common in men, while the entire
spine is more often affected in women (Quiton &
Greenspan 2007; Rollman & Lautenbacher 2001).
The study of musculoskeletal health in female den-
tists has shown that they are at higher risk of pain, from
their work, than their male colleagues. It is caused by a
specific pain syndrome, which is linked to back muscle
imbalances. Women have a greater predisposition to
musculoskeletal disorders and specifically to muscle
pain. Women should go through preemptive ergo-
nomic intervention and should be specifically trained
to reduce the risk of pain (Diaz-Caballero et al 2010).
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Sex differences in pain perception and interpretation
Musculoskeletal pain in the lower extremities,
especially in the knee, is very widespread in the rural
population of Tibet; Tibetans lead extremely hard lives
which puts extraordinary demands on their knees (Hoy
et al 2010). At younger ages, the incidence of leg pain
is the same in both sexes; however in the older popula-
tion, a higher incidence of pain has been described in
women.
Muscle pain influences activity of the upper tra-
pezius muscle in women but not in men. Women are
more susceptible to muscle pain than men (Fala et al
2008). Women are also more sensitive to back pain;
they are predisposed to specific anatomical conditions
and also have reduced spine stability. When measuring
the geometry of vertebrae, women have reduced verte-
bral sizes. Reduced stability of the spine also increases
the potential for traumatic injuries (Valachi 2008).
Gender is a significant factor in the failure of total
hip arthroplasty. Latteier et al (2011) presented a study
involving 644 women and 719 men after arthroplasty.
Arthroplasty revision was far more common in women
than in men. High knee adduction, which was observed
more often in women compared to men, can increase
the risk for development of osteoarthritis and disorders
of the anterior cruciate ligament.
Temporomandibular disorders
Women also have a higher prevalence of pain in the
temporomandibular joint (Goncalves et al 2010). A
higher prevalence of temporomandibular disorders
(TMD) has been found in violinists who opened their
mouth to stabilize the violin during playing (Rodr-
guez-Lozano et al 2010). Examination of the temporo-
mandibular joint should be part of rheumatological
examinations; such examinations could lead to better
pain management (Alonso-Blanco et al 2012).
Rusanen and colleagues (2011) discussed the charac-
teristics of TMD in association with typical facial pain,
which occurs during biting, and oral health in patients
with severe occlusions, a conditioon more common
in women. Disorders of occlusion are directly related
to oral health and quality of life. Patients with severe
occlusion also have temporomandibular disorders and
facial pain with decreased quality of oral health.
An American study, Plesh et al (2011), describes
TMD and disorders of muscle tone along with other
comorbid pains. Pain from temporomandibular joint
disorders were usually associated with 2 or 3 other
comorbid pains and only rarely occured alone.
TMD pain is also related to deafness. TMD is far
more common in women than in men. Mild forms of
this disorder are associated with limitations in opening
of the mouth, with ear abnormalities, and with normal
audiograms. However, severe TMD involves hearing
loss of high and low frequencies (Kitsoulis et al 2011).
A lower prevalence of TMD in men has been explained
based on the protective effects of testosterone (Fisher
et al 2007).
Pain measurement in patients with painful diabetic
peripheral neuropathy has clinical significance for accu-
rate diagnosis of the disease. The intensity of trigemi-
nal pain in women was associated with lower levels of
glycated hemoglobin (Petriconis et al 2010). Orofacial
pain was more common in women than in men, with
higher pain thresholds correlated with higher glucose
levels and glycated hemoglobin (Arap et al 2010).
Dental pain
Sex differences relative to dental pain and fear of dental
pain can be caused by psychogenic, psychological and
psychosomatic factors. Although a single application of
both pentazocine and naloxone induced greater anal-
gesia than placebo, ontological analgesia was greater
when pentazocine and naloxone were administered
together. Analgesia was greater in women than in men
for this type of pain; however pentazocine alone had
the opposite effect (Ryan et al 2008).
Ergonomic factors cause pain in dentists. Their job
puts long term stress on overloaded skeletal muscles
(Doyal & Naidoo 2010). Dentists suffer from muscle
pain in the back, neck, shoulders and hands. Therefore,
it is necessary to devise an occupational health program
that seeks to modify their lifestyle; this is especially true
for women (Diaz-Caballero et al 2010).
Headache
Headache is another pain state which is more common
in women than in men. Migraine has the highest inci-
dence at about age 40 and then decreases, regardless
of race or ethnicity (Peterlin et al 2011). Frequency
of migraine attacks is very dependent on hormonal
cycles, but psychosocial factors also play an important
role. Epidemiological findings show that women have a
higher degree of incapacity, relative to work, and more
psychiatric comorbidities associated with headaches
than men.
Hunt et al (2011) studied the association between
gender and frequency of medical consultations for back
pain and headaches. Women consulted more often for
general symptoms (e.g. headache and back pain) than
men.
Chest pain
Post-sternotomic chronic pain is a very intense sternal
pain syndrome. It is often accompanied by headaches,
neck pain, back pain and pain in the upper extremities.
We do not know the exact cause of this type of pain, but
it is more common in women than in men (van Leer-
sum et al 2010).
According to the study Monika (Kirchberger et al
2011), women suffer far more pain on the left side than
with the other syndromes. Gender differences were
described for chest pain, pain in the right shoulder or
synkopias but no differences were found relative to
acute myocardial infarction, from the point of view of
pain intensity.
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Richard Rokyta, Anna Yamamotov
Abdominal and pelvic pain
Results of pain treatment in emergency department
patients with acute abdominal pain indicate that
women have less sensitivity to opioids and therefore
oligoanalgesia is a problem; opioids should be used as
part of a combination therapy, as shown experimentally
(Banz et al 2010).
Irritable bowel syndrome (IBS) is also a gender and
lifestyle dependent disease. Less important, secondary
factors, include environmental factors, psychosocial
stressors, gastrointestinal infections, antibiotics, and
food (Spiller 2011).
Pelvic pain can be very intense. Since this type of
pain differs in men and women, it must be treated dif-
ferently with respect to reduced sensitivity to opioid
therapy in women (Savoye-Collet et al 2010). Pelvic
disorders, particularly in the posterior pelvic region
are sex dependent. Defecography has shown different
abnormalities in men and women, mainly in the recto-
cele and enterocele. Perineal disorders were observed
far less frequently in men than in women; in women
perineal protrusions were more frequent (Moise et al
2007).
Sex differences predict quality of life in patients with
cancer pain. Sex is an accessory factor in the character-
istics of quality of life, but the differences between indi-
vidual patients are larger than the differences between
sexes.
Psychosocial factors
Pain is influenced by psychosocial factors which repre-
sent an integral part of cultural position, race and eth-
nicity; however, it may be changed by actual mood and
especially by psychiatric conditions such as depression.
Strong interactions exist between ethnicity, religiosity,
and gender and pain anticipation.
Graham et al (2011) tried to ascertain which health
conditions make people most unhappy. They found that
anxiety and pain had a stronger impact than physical
conditions, since people adapt better to single specific
stresses than to complex uncertain stresses. The impact
of negative emotions is much broader than that of posi-
tive emotions.
Women are far more self-critical. Self-criticism inter-
acts with morbidity, including depression, and repre-
sents an important factor of affective pain. Depression
also increases in parallel with increasing self-criticism.
Women are more prone to catastrophization than
men (Edwards et al 2003). The impact of catastrophiza-
tion on pain is expressed more in clinical pain than in
experimental pain.
Darnall et al (2010) published a pilot study on the
development of inflammatory responses in people with
chronic pain. Inflammatory responses that coincided
with negative emotional experiences were more intense
and of longer duration in women with chronic pain than
in men. In the first phase of pain, the duration of pain
symptoms depends on cytokine responses which repre-
sent critical factors for the future development of pain.
Fillingim et al (2003b) described perception of
chronic pain to be dependent on patient marital status.
Men who lived alone had increased perception of
pain and impaired quality of life; while women living
and feeling alone, had lower pain tolerance, they also
reported that pain interfered more with daily tasks such
as walking or lifting. Single women also used more
opioid medications. Men and women living alone had
higher pain scores during testing, something which
should be taken into account during pain management.
Various chronic pain conditions can be more dan-
gerous for women than for men and psychological
stress, which involves sympathetic activation, is the
cause (Vierck et al 2008).
Haskell et al (2010) described gender differences
in the incidence of depression in post-traumatic stress
syndrome, pain, obesity and sexual trauma in USA
veterans who had fought in Iraq and Afghanistan. The
most important sex differences were found associated
with a positive screening for MST (military sexual
trauma), depression, obesity and post-traumatic stress
disorder. These findings are valuable with regard to
pain perception.
Robinson et al (2005) studied the effect of gender
and fear on temporal summation of pain. Summation
of pain is a phenomenon that occurs in both men and
women. After repeated thermal stimulation, women
felt greater pain intensity compared to men. Temporal
summation is affected by anxiety and social learning,
which determines the role of men and women regard-
ing attitudes toward pain.
Jensen et al (2011) showed that fear was a significant
predictor in women with back pain and that previous
back pain may serve as a predictor for monitoring pain
in the upper limbs. Previous pain intensity seems to be
the main factor that influences present acute pain and
prescription of analgesic effectiveness (Dao & LeResche
2000; LeResche 2011).
Ethnicity
Women have a different biological mechanism for pain
and ethnic subgroups have different mechanisms for
perception and response to pain (Jackson et al 2002).
Race and sex play an important role in low back
pain. Pain is reported to be more intense in white and
Hispanic women throughout life; it is also more intense
for non-white men in their sixties. Occurrence of neck
pain increases until age 60 and is more common among
younger Hispanic women; in later life this pain becomes
more common in men, with the highest frequency in
the non-white population (Green & Hart-Johnson
2010).
An interesting study, conducted by neurologists and
algesiologists from Toronto, showed that in addition to
gender, ethnicity was also an important factor. Several
U.S. publications show different results when tested for
131 Act Nerv Super Rediviva Vol. 55 No. 3 2013
Sex differences in pain perception and interpretation
pain; differences were found in white Americans and
African-Americans living in the same social and geo-
graphical environment. African-Americans felt more
pain than white Americans, which was especially true
in women. It is necessary to provide further studies
before an accurate explanation of these differences can
be offered (Campbell et al 2008; Hastie et al 2004; Sato
et al 2011).
Research in animal models of pain
Responses to prolonged painful thermal stimulations
have been tested in Long Evans and Sprague-Dawley
rat strains. In female rats, cold nociceptive stimulation
was more aversive than hot stimulation whereas oppo-
site results were found in male rats (Alabas et al 2012b;
Filingim et al 1999; Kakeda & Ishikawa 2011).
Stress during the prenatal developmental period
can also change sensitivity to pain. When pregnant rats
had formalin injected into their paw, postnatal testing
of their offspring showed that prenatally stressed male
rats were more sensitive to pain than female rats (La
Prairie & Murphy 2007).
On the other hand, female rats were more sensitive to
inflammatory processes. Females, damaged by neonatal
hypoxia and undernutrition, developed in adulthood,
greater inflammatory hyperalgesia after intraplantar
injection of carrageenin or Freunds adjuvant compared
to equally injured males.
Males were found to be more sensitive to morphine
than females and females were found to be more sensi-
tive to pain and less sensitive to opioids, therefore it is
important to combine two analgesics such as gabapentin
and tramadol (Gaumond et al 2007). Antinociceptive
effects of tramadol and gabapentin were investigated in
mice using the tail-flick test (tramadol was administered
at a dose of 60 mg/kg, gabapentin at a dose of 75 mg/
kg). ED50 for antinociceptive effects in tramadol were
lower in males than in females, females were less sensi-
tive to this drug. Conversely, gabapentin had only lim-
ited antinociceptive effects in both males and females.
When both drugs were combined, no sex differences
were observed (Dai et al 2008; Gioiosa et al 2008).
Morphine preferentially activates the pathway
between periaqueductal gray matter and the rostral
ventromedial medulla (RVM). Activation of this axis is
greater in males than in females and this is probably the
cause of morphine induced antinociception that is fre-
quently observed in males. Periaqueductal gray matter
in the midbrain and its descending projections to the
RVM constitute a basic circuit for opioid analgesia. The
effect is also sexually dimorphic (Popescu et al 2010;
Loyd et al 2007).
The antinociceptive effects of morphine are stronger
in rodent males than females. This was demonstrated
using rats, when animals of both sexes had morphine
injected into the ventrolateral periaqueductal gray
matter. Male rats were compared with females during
their estrous cycle; the observed antinociceptive effects
were greater in males than in females during proestrus,
followed by estrus and metestrus (Craft 2007).
Similar results were observed in the sensitivity of
mice to morphine. Nociception was tested using the hot
plate test and gonadal males (genotype XX and XY) and
in gonadal females (genotype XX and XY). Males were
more sensitive to morphine than females and the sen-
sitivity was always Y chromosome dependent. There-
fore, genes localized on X or Y chromosomes could be
responsible for sexual dimorphism in pain perception
and analgesia. Hormones affect sensitivity to opioids
far less than expected (Gioiosa et al 2008).
Modulation of morphine analgesia, by estrogen, in
visceral pain in female rats can be mediated by supra-
spinal and peripheral factors. Although females are less
sensitive to morphine-induced analgesia than males;
after ovariectomy or estrogen substitution, females
have stronger responses to morphine than males. In
intact females, estrogen is one of the key factors that
contribute to sex differentiation of opioid analgesia
(Ji et al 2011).
Cataldo et al (2010) studied the effect of ventro-
medial and medial preoptic hypothalamic lesions
induced by ibotenic acid. These nuclei are involved in
morphine-induced analgesia in female rats but not in
males. In intact females, ventromedial hypothalamic
nuclei and medial preoptic nuclei respond with tonic
inhibition that originates from endogenous pain inhibi-
tory circuitry. This is related to levels of circulating sex
hormones, which has been demonstrated in ovari-
ectomized rats. Excitotoxic destruction of estrogen
receptors weakens the analgesic response to systemic
administration of morphine.
There are sex differences in activity and modulation
of N-methyl-D-aspartate receptors (NMDAR) in dorsal
root ganglia (DRG). Beta estradiol has been shown to
modulate NMDA receptor activity in DRG neurons.
Electrical currents of NMDA receptors in these neu-
rons were three times longer in females than in males
(Butkevich et al 2007a,b).
Endothelin 1 is a vasoactive peptide which is released
into the systemic circulation after stress and pain caused
by cold. It is formed locally in tissues after injury or dis-
ease. Endothelin 1 is also produced during spontaneous
nociceptive behavior and after mechanically induced
allodynia. Release of endogenous endothelin is greater
in younger compared to older organisms. Endothelin
1 induces mechanical allodynia in all age groups but is
produced more in young females (McKelvy et al 2007).
Modulation of visceral pain is dependent on BDNF
(brain-derived neurotrophic factor) that facilitates vis-
ceral pain in female rats, but has the opposite effect in
males. With regard to clinical pain management there
is a significant difference (Li et al 2010a).
Neuregulin I was discovered in the spinal cord. It
is a growth factor and pro-nociceptive cytokine that
is modulated by progesterone in the spinal cord. In
132 Copyright 2013 Activitas Nervosa Superior Rediviva ISSN 1337-933X
Richard Rokyta, Anna Yamamotov
females, neuregulin I is one of many factors responsible
for central sensitization during ongoing pain. Thus
progesterone-dependent regulation of neuronal or glial
neuregulin production in females could be the cause of
sexual differentiation in nociception and increased pain
perception (LaCroix-Fralish et al 2008).
Belinger et al (2007) showed that capsaicin-sensi-
tive neurons in inflammatory TMD produce different
nociceptive responses in male and female rats. Capsa-
icin-sensitive neurons are partially responsible for the
transmission of acute nociceptive pain. As nociception
in the inflamed region is gender specific, females are
more susceptible to the development of this effect.
Genetic studies show which genes are responsible for
sexual dimorphism in pain perception. Genes express-
ing neuregulin I and its high affinity receptor RB4, as
well as genes for tachykinin 1 and metabotropic glu-
tamate receptor 6, have been shown to be specific and
are increasingly up-regulated in damaged L5 roots in
females (LaCroix-Fralish et al 2008).
In animal research, both gender and strain play
important roles. Just as in humans, mice and rats also
demonstrate psychosocial effects (Edwards et al 2003;
Paulson et al 1998).
Conclusion
From the above survey it can be concluded that pain
perception is different in males and females. Differ-
ences have been found in the pathophysiology, patho-
genesis and clinical manifestations of diseases. These
differences are important with regard to treatment,
which should be gender-specific. These fundamental
differences also relate to ontogenetic factors. Child-
hood, adulthood, and elderly populations of males and
females respond differently to pain and its treatment,
therefore this should be taken into account during clini-
cal pain management.
Acknowledgements
The work was supported by Charles University project
Prvouk P34.
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